Biomarkers.

Background: Sleep disturbances have been identified as a risk factor for developing dementia. The hypothalamus is involved in sleep regulation and may be affected early by neurodegeneration. Our aim was to investigate the relationship between subjective sleep and hypothalamic structure in adults at higher risk of developing dementia.

Biomarkers.

White matter hyperintensities (WMH) are highly prevalent in aging and Alzheimer's disease (AD) and typically attributed to vascular damage and cerebral small vessel disease. Yet, several lines of evidence from the literature emphasize the heterogeneity in the mechanisms leading to WMH, notably in AD, suggesting that WMH may be partly attributable to AD. Thus, firstly, neuropathological studies demonstrate heterogeneity in WMH histology, with indications of a link between tau pathology, Wallerian degeneration, and WMH severity.

A phase I clinical trial of intrahepatic artery delivery of TG6002 in combination with oral 5-fluorocytosine in patients with liver-dominant metastatic colorectal cancer.

Background: Effective treatment for patients with metastatic cancer is limited, particularly for colorectal cancer patients with metastatic liver lesions (mCRC), where accessibility to numerous tumours is essential for favourable clinical outcomes. Oncolytic viruses (OVs) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoural administration routes.

Methods: We conducted a multi-centre, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral pro-drug 5-fluorocytosine to fifteen mCRC patients.

Biomarkers.

Background: Neuropsychiatric symptoms (NPS), including depression and circadian rhythm disruptions, are early non-cognitive markers along the Alzheimer's Disease (AD) continuum. These pathological states are thought to resemble AD pathogenesis, both of which are characterized by a marked decline in adult hippocampal neurogenesis.

Method: 96 elderly participants divided into three groups based on the global depression scale, neuropsychiatric inventory, clinical dementia rating, and mini-mental status examination.

Biomarkers.

Background: Patterns of regional atrophy and hypometabolism have been observed in dementia with Lewy bodies (DLB). However, determinants of regional vulnerability to structural and functional neurodegeneration remain largely unexplored. First, we investigated the association between regional gene expression and grey matter volumes in probable DLB patients.

Biomarkers.

Background: Tau-PET imaging allows in-vivo detection of neurofibrillary tangles. One tau-PET tracer (i.e.

Biomarkers.

Background: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neurodegenerative disease that is often comorbid with Alzheimer's disease (AD) and for which there are no reliable specific chemical or PET biomarkers available. Recent progress in disease-modifying treatments for AD elevates the need for reliable in vivo detection of LATE and other comorbid neurodegenerative diseases. The promise of postmortem and antemortem MRI studies in LATE is that they will lead to the discovery of patterns of neurodegeneration associated with TDP-43 pathology that could be reliably detected in vivo and used as a biomarker of LATE.

Optimal Word Reading Rate as Evidenced by Frequency-tagging Electrophysiology.

Fast periodic visual stimulation (FPVS) coupled with EEG has been used for a decade to measure word-selective neural responses in (a)typical adults and developmental readers. Here, we used this FPVS-EEG approach to evaluate suitable and optimal stimulation frequency rates for prelexical and lexical word-selective responses and relate these rates to typical reading speed and interindividual variability in reading performance. EEG was recorded in 41 healthy adults who viewed words inserted periodically (1 Hz) at four different stimulation frequency rates (4 Hz, 6 Hz, 10 Hz, and 20 Hz).

Biomarkers.

Background: Locus coeruleus (LC) imaging using neuromelanin-sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer's Disease (AD). Although automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on a single template built in a standardized space and/or depend on a number of voxels to be accounted that is defined a priori. Thus, these algorithms make it impossible to perform direct volumetric analyses and do not properly account for inter-individual anatomical variability.

Biomarkers.

Background: Increased stress, a proposed risk factor for Alzheimer's disease (AD), is associated with increased brain and cognitive vulnerabilities in older populations, which may be different in women and men.

Objective: To examine cross-sectional associations between circulating stress hormones (epinephrine, norepinephrine, cortisol, dehydroepiandrosterone sulfate (DHEAS), and DHEAS/cortisol ratio) and multimodal measures of brain health and cognition sensitive to AD.

Method: 132 cognitively unimpaired older participants without clinical depression (age = 74.

Biomarkers.

Background: Tau pathology and neurodegeneration in the medial temporal lobe (MTL) are highly associated in Alzheimer's Disease (AD). However, the spatial pattern of neurodegeneration, contribution of individual tau inclusion types, and influence of MTL co-pathologies (i.e.

Biomarkers.

Background: The immune complement system is key to the elimination of redundant neural connections in the brain through a process called synaptic pruning. In neurodegenerative diseases such as Alzheimer's disease (AD), this system may result in excessive synapse loss, leading to brain atrophy and cognitive impairment. While increased cerebrospinal fluid (CSF) levels of complement proteins have been observed in patients with AD dementia, no studies have yet investigated the role of complement in the pre-symptomatic phase of AD, nor throughout its progression.

Biomarkers.

Background: Typical Alzheimer's disease (AD) and Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) are two neurodegenerative diseases that present with a similar initial amnestic clinical phenotype but have distinct proteinopathies. AD is characterised by ß-amyloid plaques and intraneuronal neurofibrillary tangles, while LATE is characterised by abnormal neuronal TDP-43 protein. With reference to the prion-like hypothesis regarding the propagation of proteinopathies, investigating white matter fibre bundle alterations could provide new insights into the propagation pathways of specific proteinopathies.

Biomarkers.

Background: Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Its underlying mechanisms remain elusive and specific mechanism-based drugs are lacking.

Method: We integrated more than 2,800 CSF and 4,600 plasma pQTL, derived from the largest proteomic studies so far (SOMAscan 7k and 4k; in up to 35,559 individuals), and the two most prevalent MRI-markers of cSVD (MRI-cSVD, white matter hyperintensities and perivascular spaces burden; in up to 48,454 individuals) in a Mendelian Randomization (MR) framework to identify causal and druggable targets for cSVD.

Biomarkers.

Background: It is estimated that up to 80% of people with Alzheimer's disease (AD) may have some form of anosognosia. Anosognosia also constitutes a major source of stress for caregivers as it delays diagnosis and affects compliance with treatment. Here, we aimed to explore whether and how early anosognosia and caregiver burden could independently serve as indicators for identifying patients at risk of converting to AD.

Short-term exposure to PM pollution in Iran and related burden diseases.

The objective of this study was to estimate the health effects attributed to PM exposure in southwest of Iran. In order to estimate HA-CVD, HA-RD, LC-M, I-As in children, RAD, and WDL, the exposure-response function method was used. The annual mean of PM regularly exceeded 5.

Biomarkers.

Background: Cerebrovascular reactivity (CVR) is implicated in the progression of dementia, though the underlying mechanisms is not understood. This study examines the relationships between CVR and brain structure and cognitive decline, moderated by mid-life dementia risk.

Method: 163 participants from the Whitehall-II cohort underwent neuropsychological testing and MRI, including T1-weighted, FLAIR, and DTI sequences, at two phases (Phase-I: mean age=68.

Biomarkers.

Background: Individuals with Down Syndrome (DS) almost invariably develop Alzheimer's Disease (AD), but detecting early clinical changes is challenging due to comorbid intellectual disability, highlighting the importance of non-invasive biomarkers. Neuroimaging of the medial temporal lobe (MTL), a key site of tau pathology, shows promise as an early AD biomarker. Here, we aimed to characterise volumetric patterns of the MTL in DS across the AD clinical continuum, and define associations with AD cerebrospinal fluid (CSF) biomarkers.

Biomarkers.

Background: Recently, the development of ultra-sensitive immunoassays has allowed for the detection, in blood, of proteins related to the pathophysiology of Alzheimer's disease (AD), with phosphorylated tau (p-tau) being the most promising. However, current methods are often limited by their ability to measure one analyte, lacking the potential for discovery and inclusion of additional biomarkers with supplemental value. In this pilot study, we explored proteomic changes using the novel NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) platform, focusing on patients with mild cognitive impairment (MCI).

Biomarkers.

Background: ALZ-801 (valiltramiprosate) is an oral inhibitor of amyloid oligomer formation in development as a disease-modifying AD treatment, including a fully enrolled APOLLOE4 Phase 3 trial in 325 APOE4/4 homozygotes. A Phase 2 study is evaluating ALZ-801 effects on plasma biomarkers, brain volumes and cognitive outcomes in APOE4 carriers. Plasma p-tau reduction over 104 weeks is primary endpoint.

Public Health.

Background: Some older adults succeed in maintaining excellent cognition despite high genetic risk for Alzheimer's disease (AD), reflecting cognitive resistance (CR) to potential neuropathologies. Although the etiological factors for CR are still unknown, some literature suggests that environmental/lifestyle risk factors may contribute to offset, or at least reduce, the effect of AD-related genes on cognitive decline and dementia risk. Yet, how modifiable lifestyle and health related risk factors may promote CR in genetically at-risk individuals remains to be elucidated.

Public Health.

Background: High-income countries (HICs) are over-represented in current global dementia incidence rates, skewing estimates. Variance in diagnostic methods between HICs and low- and middle-income countries (LMICs) is speculated to contribute to the regional differences in rates. Cohort Studies of Memory in an International Consortium (COSMIC) offers a unique opportunity to address these research inequalities by harmonising data from international studies, including representation from LMICs.

Public Health.

Background: To estimate the additive associations of cardiometabolic multimorbidity (CMM) and depression on long-term cognitive trajectory in multi-regional cohorts and validate the generalizability of the findings in varying clinical settings.

Method: Data harmonization was performed across 14 longitudinal cohort studies within the Cohort Studies of Memory in an International Consortium (COSMIC) group, spanning North America, South America, Europe, Africa, Asia, and Australia. Three external validation studies with distinct settings were employed to assess generalizability.

Public Health.

Background: Dementia is a major contributor to loss of autonomy in the elderly. Every year spent with dementia results in significant medical and societal costs. Understanding secular trends of life expectancy with and without dementia would enable us to better anticipate future needs.

Public Health.

Background: Higher Mediterranean- DASH for Neurodegenerative Delay (MIND) diet scores have previously been associated with larger total brain volume (TBV) in the Framingham Offspring Study (FOS) community-based cohort. We investigated cross-sectional relationships between the MIND diet and structural brain imaging volumes and white matter hyperintensity volume (WMHV) across six community-based cohorts.

Method: We analyzed data from 3130 dementia-, stroke- and other neurological disease free adults (aged 65 to 74) who participated in the Atherosclerosis Risk in Communities (ARIC) cohort, Cardiovascular Health Study (CHS), Three City (3C) cohort, FOS cohort, Rotterdam Study (RS) or the Study of Health in Pomerania (SHIP) cohort.